The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDS-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes.
Currently available chemotherapy targets two crucial viral enzymes: HIV protease and HIV reverse transcriptase. (J. S. G. Montaner et al., Antiretroviral therapy: ‘the state of the art’ Biomed & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, Highly active retroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type, Biomed. & Pharmacother. 1999 53:73-86; E. De Clercq, New Developments in Anti-HIV Chemotherap. Curr. Med. Chem. 2001 8:1543-1572). Two general classes of RTI inhibitors have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors. Currently the CCR5 co-receptor has emerged as a potential target for anti-HIV chemotherapy (D. Chantry, Expert Opin. Emerg. Drugs 2004 9(1):1-7; C. G. Barber, Curr. Opin. Invest. Drugs 2004 5(8):851-861; D. Schols, Curr. Topics Med. Chem. 2004 4(9):883-893; N. A. Meanwell and J. F. Kadow, Curr. Opin. Drug Discov. Dev. 2003 6(4):451-461).
NRTIs typically are 2′,3′-dideoxynucleoside (ddN) analogs which must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT. After incorporation into nucleic acids the nucleoside analogs terminate the chain elongation process. HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation. Currently clinically used NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir (PMPA).
NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate-binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity (R. W. Buckheit, Jr., Non-nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq, The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV infection, Antiviral Res. 1998 38:153-179; E. De Clercq, New Developments in Anti-HIV Chemotherapy, Current medicinal Chem. 2001 8(13):1543-1572; G. Moyle, The Emerging Roles of Non-Nucleoside Reverse Transcriptase Inhibitors in Antiviral Therapy, Drugs 2001 61(1):19-26). Although over thirty structural classes of NNRTIs have been identified in the laboratory, only three compounds have been approved for HIV therapy: efavirenz, nevirapine and delavirdine.
Initially viewed as a promising class of compounds, in vitro and in vivo studies quickly revealed the NNRTIs presented a low barrier to the emergence of drug resistant HIV strains and class-specific toxicity. Drug resistance frequently develops with only a single point mutation in the RT. While combination therapy with NRTIs, PIs and NNRTIs has, in many cases, dramatically lowered viral loads and slowed disease progression, significant therapeutic problems remain. (R. M. Gulick, Eur. Soc. Clin. Microbiol. and Inf. Dis. 2003 9(3):186-193) The cocktails are not effective in all patients, potentially severe adverse reactions often occur and the rapidly reproducing HIV virus has proven adroit at creating mutant drug-resistant variants of wild type protease and reverse transcriptase. There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HIV.

Pyrimidine compounds that inhibitor HIV-1 reverse transcriptase have been disclosed (J. Guillemont et al., WO2006/035068 published Apr. 6, 2006; J. Guillemont et al., WO2006/035067 published Apr. 6, 2006; J. Guillemont et al., WO2006/045828 published May 4, 2006; J. Guillemont et al., WO2006/035369 published Apr. 6, 2006; H. A. De Kock and P. Wigerinck, WO2006/094930 published Sep. 14, 2006; H. A. De Kock and P. Wigerinck, WO2006/087387 published Aug. 24, 2006; P. A. J. Jansen et al., J. Med. Chem. 2005 48(6):1901-09; K. Das et al., J. Med. Chem. 2004 47(10):2550-2660; J. Guillemont et al., J. Med. Chem. 2005 48(6):2072-2079). Pyrimidine compounds reported to exhibit effective inhibition of HIV reverse transcriptase include TMC125 (8a) and TMS120 (8b)